The Effect of Early-Life Environmental Exposures on Disease Phenotype and Clinical Course of Crohn's Disease in Children

Lindoso, Lívia; Mondal, Kajari; Venkateswaran, Suresh; Somineni, Hari K.; Ballengee, Cortney R.; Walters, Thomas D.; Griffiths, Anne M.; Noe, Joshua D.; Crandall, Wallace; Snapper, Scott B.; Rabizadeh, Shervin; Rosh, Joel R.; Leleiko, Neal; Guthery, Stephen L.; Mack, David R.; Kellermayer, Richárd; Gulati, Ajay; Pfefferkorn, Marian D.; Moulton, Dedrick E.; Keljo, David J.; Cohen, Stanley A.; Oliva‐Hemker, Maria; Heyman, Melvin B.; Otley, Anthony; Baker, Susan S.; Evans, Jonathan; Kirschner, Barbara S.; Patel, Ashish; Ziring, David; Stephens, Michael C.; Baldassano, Robert N.; Dubinsky, Marla; Markowitz, James; Denson, Lee A.; Hyams, Jeffrey; Kugathasan, Subra; Ananthakrishnan, Ashwin N.

doi:10.1038/s41395-018-0239-9

Cited by 37 publications

(24 citation statements)

References 35 publications

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“…Further clinical trials showed that smoking is an independent risk factor associated with an unfavorable outcome in CD patients [34][35][36][37][38][39]. The mechanism by which smoking alters the disease course has not been elucidated yet, but the existing evidence suggests an influence of smoking on the innate and acquired immune system and the intestinal microbiome which is supported by our findings pointing to NOD2 as a major co-variant by which smoking results in intestinal stenosis [34,36,[39][40][41][42][43].…”

Section: Plos Onesupporting

confidence: 78%

Development of a uniform, very aggressive disease phenotype in all homozygous carriers of the NOD2 mutation p.Leu1007fsX1008 with Crohn’s disease and active smoking status resulting in ileal stenosis requiring surgery

et al. 2020

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Background NOD2 variants are the strongest genetic predictors for susceptibility to Crohn's disease (CD). However, the clinical value of NOD2 on an individual patient level remains controversial. We aimed to define the predictive power of the major NOD2 mutations regarding complicated CD in a large single center cohort. Methods 1076 CD patients were prospectively genotyped for the three common CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847, followed by detailed genotypephenotype analyses. Results Overall, 434 CD patients (40.3%) carried at least one of the three main NOD2 mutations. A significantly higher minor allele frequency (15.6%) of the NOD2 frameshift mutation p. Leu1007fsX1008 (rs2066847) was seen in patients with aggressive disease compared to 8.2% in patients with mild disease (p = 2.6 x 10 −5). Moreover, a total of 54 CD patients (5.0%) were homozygous for this NOD2 frameshift mutation. 100% of these patients had ileal disease compared to 82% of NOD2 wild-type carriers (p<0.0001). In homozygous carriers of the NOD2 frameshift mutation, 87% presented with ileal stenosis, 68.5% had fistulas, and 72.2% required CD-related surgery despite immunosuppressive therapy in 87% of

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Section: Plos Onesupporting

confidence: 78%

Development of a uniform, very aggressive disease phenotype in all homozygous carriers of the NOD2 mutation p.Leu1007fsX1008 with Crohn’s disease and active smoking status resulting in ileal stenosis requiring surgery

et al. 2020

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“…Environmental factors, which directly affects intestinal microbiota composition, have been pointed out as one of the key players in the pathogenesis of IBD. In this regard, early life exposure to breastfeeding and maternal smoking during pregnancy, have been inversely and positively correlated to disease outcome in CD, respectively (Lindoso et al, 2018). Accordingly, patients with UC (Elinav et al, 2011) tend to have a better outcome when treated with microbial-based therapies (i.e., antibiotics, FMT, and probiotics).…”

Section: Intestinal Dysbiosis In the Pathogenesis Of Ibdmentioning

confidence: 99%

Microbial-Based Therapies in the Treatment of Inflammatory Bowel Disease – An Overview of Human Studies

2019

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Inflammatory bowel disease (IBD) is a group of multifactorial and inflammatory infirmities comprised of two main entities: Ulcerative colitis (UC) and Crohn’s disease (CD). Classic strategies to treat IBD are focused on decreasing inflammation besides inducing and extending disease remission. However, these approaches have several limitations such as low responsiveness, excessive immunosuppression, and refractoriness. Despite the multifactorial causality of IBD, immune disturbances and intestinal dysbiosis have been suggested as the central players in disease pathogenesis. Hence, therapies aiming at modulating intestinal microbial composition may represent a promising strategy in IBD control. Fecal microbiota transplantation (FMT) and probiotics have been explored as promising candidates to reestablish microbial balance in several immune-mediated diseases such as IBD. These microbial-based therapies have demonstrated the ability to reduce both the dysbiotic environment and production of inflammatory mediators, thus inducing remission, especially in UC. Despite these promising results, there is still no consensus on the relevance of such treatments in IBD as a potential clinical strategy. Thus, this review aims to critically review and describe the use of FMT and probiotics to treat patients with IBD.

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“…In patients with inflammatory bowel disease, dendritic cells are attracted and accumulate at the inflammatory sites. Dendritic cells from mesenteric lymph nodes of patients with Crohn's disease preferentially induce the Th1 response 67 . And the myeloid dendritic cells from mesenteric lymph nodes of patients with Crohn's disease produce high levels of interleukin‐23 and low levels of interleukin‐10 150 .…”

Section: Introductionmentioning

confidence: 99%

Review article: impact of cigarette smoking on intestinal inflammation—direct and indirect mechanisms

Παπουτσοπουλου

Satsangi

Campbell

et al. 2020

Aliment Pharmacol Ther

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The Effect of Early-Life Environmental Exposures on Disease Phenotype and Clinical Course of Crohn's Disease in Children

Cited by 37 publications

References 35 publications

Development of a uniform, very aggressive disease phenotype in all homozygous carriers of the NOD2 mutation p.Leu1007fsX1008 with Crohn’s disease and active smoking status resulting in ileal stenosis requiring surgery

Development of a uniform, very aggressive disease phenotype in all homozygous carriers of the NOD2 mutation p.Leu1007fsX1008 with Crohn’s disease and active smoking status resulting in ileal stenosis requiring surgery

Microbial-Based Therapies in the Treatment of Inflammatory Bowel Disease – An Overview of Human Studies

Review article: impact of cigarette smoking on intestinal inflammation—direct and indirect mechanisms

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